Lgr4 and Lgr5 drive the formation of long actin-rich cytoneme-like membrane protrusions

Abstract

Embryonic development and adult tissue homeostasis require precise information exchange between cells and their microenvironment to coordinate cell behavior. A specialized class of ultra-long actin-rich filopodia, termed cytonemes, provides one mechanism for this spatiotemporal regulation of extracellular cues. We provide here a mechanism whereby the stem cell marker Lgr5, and its family member Lgr4, promote the formation of cytonemes. Lgr4/5-induced cytonemes exceed lengths of 80 µm, are generated through stabilization of nascent filopodia from an underlying lamellipodial-like network, and functionally provide a pipeline for the transit of signaling effectors. As proof-of-principle, we demonstrate that Lgr5-induced cytonemes act as conduits for cell signaling by demonstrating that the actin-motor and filopodial cargo carrier protein Myosin X (Myo10) and the GCPR signaling effector ß-arrestin-2 (Arrb2) transit into cytonemes. This work delineates a biological function for Lgr4/5 and provides the rationale to fully investigate Lgr4/5 function and cytonemes in mammalian stem cell and cancer stem cell behavior.